Comparing the diagnostic performance of QuantiFERON-TB Gold Plus with QFT-GIT, T-SPOT.TB and TST: a systematic review and meta-analysis

Background QuantiFERON-TB Gold Plus (QFT-Plus) is an important test that has emerged in recent years for detecting TB infection. We conducted a review to compare the sensitivity, specificity and positive rate of QFT-Plus with that of QuantiFERON-TB Gold In-Tube (QFT-GIT), T-cell spot of tuberculosis assay (T-SPOT.TB) and Tuberculin test (TST). Methods PubMed and Embase were searched, without language restrictions, from 1 January 2015 to 31 March 2022 using “Mycobacterium tuberculosis Infections” and “QuantiFERON-TB-Plus” as search phrases. We estimated the sensitivity from studies of patients with active tuberculosis, specificity from studies of populations with very low risk of TB exposure, and positive rate from studies of high-risk populations. The methodological quality of the eligible studies was assessed, and a random-effects model meta-analysis was used to determine the risk difference (RD). We assessed the pooled rate by using a random-effects model. This study was registered in PROSPERO (CRD 42021267432). Results Of 3996 studies, 83 were eligible for full-text screening and 41 were included in the meta-analysis. In patients with active TB, the sensitivity of QFT-Plus was compared to that of QFT-GIT and T-SPOT.TB, respectively, and no statistically differences were found. In populations with a very low risk of TB exposure, the specificity of QFT-Plus was compared with that of QFT-GTI and T-SPOT.TB, respectively, and no statistically differences were found. Two studies were eligible to compare the specificity of the QFT-Plus test with that of the TST test, and the pooled RD was 0.12 (95% CI 0.02 to 0.22). In high-risk populations, 18 studies were eligible to compare the positive rate of the QFT-Plus test with that of the QFT-GIT test, and the pooled RD was 0.02 (95% CI 0.01 to 0.03). The positive rate of QFT-Plus was compared with that of T-SPOT.TB and TST groups, and no statistically differences were found. Conclusions The diagnostic performance of QFT-Plus was similar to that of QFT-GIT and T-SPOT.TB, but was slightly more specific than TST. Supplementary Information The online version contains supplementary material available at 10.1186/s12879-023-08008-2.


Protocol and registration
5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number.

4
Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.

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Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

5
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

5, Table S2
Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).

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Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

6
Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. 6

Risk of bias in individual studies
12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data 7 3 synthesis.
Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). 7 Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I 2 ) for each meta-analysis.

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Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).

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Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified.

Study selection
17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.

8
Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.

8
Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment Figure S15-S17 Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot.
8-11, Figure S1-S8 Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency.

8-11
Risk of bias across studies 22 Present results of any assessment of risk of bias across studies. Figure S15-S19 Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression. Table S18 and Figure  S15-S19

DISCUSSION
Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).

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Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).

13-14
Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research.   Active TB They were all tested by sputum culture and showed to be positive.
The population included in this study had sputum culture tests that were not positive, but had other clinical tests that were positive 1. Latent infection and normal population not fully excluded.
Head-tohead test The aim of this study was to compare QFT-PLUS with QFT-GIT and T-SPOT.TB, each participant was tested within 3 days.
The aim of this study was to compare QFT-PLUS with QFT-GIT and T-SPOT.TB, but each participant was tested within 3-4 weeks or no time interval between the two tests was referenced.
1. The time interval between tests was more than 4 weeks. 2. It is not the purpose of this article to compare QFT-PLUS with QFT-GIT and T-SPOT.TB, and there is no reference to the time interval between these tests. 3. Only QFT-PLUS positive patients were tested for QFT-GIT or T-SPOT.TB, or only QFT-GIT or T-SPOT.TB positive patients were tested for QFT-PLUS. The aim of this study was to compare QFT-PLUS with QFT-GIT, T-SPOT.TB and TST, but each participant was tested within 3-4 weeks or no time interval between the two tests was referenced.
1. The time interval between tests was more than 4 weeks. 2. It is not the purpose of this article to compare QFT-PLUS with QFT-GIT, T-SPOT.TB and TST, and there is no reference to the time interval between these tests. 3. Only QFT-PLUS positive patients were tested for QFT-GIT or T-SPOT.TB or TST, or only QFT-GIT or T-SPOT.TB or TST positive patients were tested for QFT-PLUS. The aim of this study was to screen for LTBI, but there was no reference to whether active and/or suspected cases of TB were excluded.
1. Active and/or suspected cases are not excluded.
2. The purpose of this article is not to screen for LTBI and there is no reference to whether active tuberculosis and/or suspected cases have been excluded 3. Only QFT-PLUS positive, QFT-PLUS negative, QFT-GIT, T-SPOT.TB and TST positive, or QFT-GIT, T-SPOT.TB and TST negative people were included Head-tohead test The aim of this study was to compare QFT-PLUS with QFT-GIT, T-SPOT.TB and TST, each participant was tested within 3 days.
The aim of this study was to compare QFT-PLUS with QFT-GIT, T-SPOT.TB and TST, but each participant was tested within 3-4 weeks or no time interval between the two tests was referenced.
1. The time interval between tests was more than 4 weeks. 2. It is not the purpose of this article to compare QFT-PLUS with QFT-GIT, T-SPOT.TB and TST, and there is no reference to the time interval between these tests. 3. Only QFT-PLUS positive patients were tested for QFT-GIT or T-SPOT.TB or TST, or only QFT-GIT or T-SPOT.TB or TST positive patients were tested for QFT-PLUS. We excluded studies that QFT-PLUS was not compared with QFT-GIT, T-SPOT.TB and TST 3.We excluded the studies that no comparator. 4. We excluded the studies that multiple comparisons were made. Flow and outcome 1.We excluded the studies that no full text available. 2.We excluded studies with a sample size of less than 10. Table S8：QUADAS-2 adapted quality assessment criteria for patients with active TB Patient select bias Q1: Was a consecutive or random sample of patients enrolled?
We scored "Yes" if a consecutive or random sample of eligible patients was Enrolled; "No" if patients were selected by convenience; and "Unclear" if the study did not report the manner in which patients were enrolled. Q2: Were all patients included have gold standard testing?
We scored "Yes" if all patients received the gold standard; "No" if there are patients does not receive the gold standard and other clinical tests prove negative or no clinical tests prove; and "Unclear" if there are patients who did not receive the gold standard, but other clinical tests proved positive. Q3: Did the study have appropriate exclusions?
We scored "Yes" if current active TB and people with TB symptom were excluded, or they were grouped separately, or the definition of LTBI was stated as asymptomatic; "No" if it was unclear that active TB and people with TB symptom were excluded; and "Unclear" if only active TB or people with TB symptom were excluded or grouped. Test conduct bias Q4: Was the study conducted to compare QFT-PLUS with QFT-GIT, T.SPOT.TB and TST tests??
We scored "Yes" if the study was conducted to compare QFT-PLUS with QFT-GIT, T.SPOT.TB and TST tests?, "No" if the study was not conduced to compare QFT-PLUS with QFT-GIT, T.SPOT.TB and TST tests?; "Unclear" if this was not stated or stated inadequately. Q5: If a threshold is used, was it confirmed beforehand?
We scored "Yes" if the threshold values are used and predetermined, "No" if no prior determination; "Unclear" if there is no description. Q6: Was how the tests were conducted and interpreted adequately described?
We scored "Yes" if the tests were conducted and interpreted adequately described, such as the cut-off, time interval of the results were read, and manufacturer information, or "performed as the manufacturer's guidelines" was stated; and "No" if those information were not stated or stated inadequately. Q7: Was there an appropriate interval between QFT-PLUS with QFT-GIT, T.SPOT.TB and TST tests? We scored "Yes" if the two tests were paired or performed within 3 days, or "paired" comparison, "head-to-head" comparison was reported, and "No" if the interval was more than 3 days and less than 4 weeks; "Unclear" if this was not stated. Flow and outcome Q8: Were the results of two tests interpreted without knowledge of each other? We scored "Yes" if the results of two tests were interpreted without knowledge of each other, or one test was interpreted blinded to another; "No" if blinding to test results were not done; and "Unclear" if this was not stated. Q9: Were all patients included in the analysis? We answered this question by comparing the number of participants included in the study and the number of individuals included in the 2x2 tables, test agreement data, or flow diagram. We scored 'Yes' if the number of participants enrolled was stated and corresponded to the number included in the analysis or if exclusions were adequately described. We scored "No" if there were participants missing or excluded from the analysis and there was no explanation given. We scored "Unclear" if we could not tell, e.g. because the number of participants enrolled and/or number of participants included in the analysis was not clearly stated.   Table S10：QUADAS-2 adapted quality assessment criteria for populations with very low risk of TB exposure Patient select bias Q1: Is the population included in this study at little or no risk of infection with tuberculosis?
We scored "Yes" if they live and work in an environment where they are not exposed to TB; "No" if they have exposure to TB; and "Unclear" if the study did not report. Q2: Was a consecutive or random sample of patients enrolled?
We scored "Yes" if a consecutive or random sample of eligible patients was Enrolled; "No" if patients were selected by convenience; and "Unclear" if the study did not report the manner in which patients were enrolled. Q3: Did the study have appropriate exclusions?
We scored "Yes" if current active TB and people with TB symptom were excluded, or they were grouped separately, or the definition of LTBI was stated as asymptomatic; "No" if it was unclear that active TB and people with TB symptom were excluded; and "Unclear" if only active TB or people with TB symptom were excluded or grouped. Test conduct bias Q4: Was the study conducted to compare QFT-PLUS with QFT-GIT, T.SPOT.TB and TST tests??
We scored "Yes" if the study was conducted to compare QFT-PLUS with QFT-GIT, T.SPOT.TB and TST tests?, "No" if the study was not conduced to compare QFT-PLUS with QFT-GIT, T.SPOT.TB and TST tests?; "Unclear" if this was not stated or stated inadequately. Q5: Was how the tests were conducted and interpreted adequately described?
We scored "Yes" if the tests were conducted and interpreted adequately described, such as the cut-off, time interval of the results were read, and manufacturer information, or "performed as the manufacturer's guidelines" was stated; and "No" if those information were not stated or stated inadequately. Q6: Was there an appropriate interval between QFT-PLUS with QFT-GIT, T.SPOT.TB and TST tests? We scored "Yes" if the two tests were paired or performed within 3 days, or "paired" comparison, "head-to-head" comparison was reported, and "No" if the interval was more than 3 days and less than 4 weeks; "Unclear" if this was not stated. Q7: If a threshold is used, was it confirmed beforehand? We scored "Yes" if the threshold values are used and predetermined, "No" if no prior determination; "Unclear" if there is no description. Flow and outcome Q8: Were the results of two tests interpreted without knowledge of each other? We scored "Yes" if the results of two tests were interpreted without knowledge of each other, or one test was interpreted blinded to another; "No" if blinding to test results were not done; and "Unclear" if this was not stated. Q9: Were all patients included in the analysis? We answered this question by comparing the number of participants included in the study and the number of individuals included in the 2x2 tables, test agreement data, or flow diagram. We scored 'Yes' if the number of participants enrolled was stated and corresponded to the number included in the analysis or if exclusions were adequately described. We scored "No" if there were participants missing or excluded from the analysis and there was no explanation given. We scored "Unclear" if we could not tell, e.g. because the number of participants enrolled and/or number of participants included in the analysis was not clearly stated.   Table S12：QUADAS-2 adapted quality assessment criteria for high-risk groups Patient select bias Q1: Was the study conducted to screen for LTBI?
We scored "Yes" if the study was conduced to screen for LTBI; and "No" if the study was not conduced to screen for LTBI; "Unclear" if this was not stated or stated inadequately. Q2: Was a consecutive or random sample of patients enrolled?
We scored "Yes" if a consecutive or random sample of eligible patients was Enrolled; "No" if patients were selected by convenience; and "Unclear" if the study did not report the manner in which patients were enrolled. Q3: Did the study have appropriate exclusions?
We scored "Yes" if current active TB and people with TB symptom were excluded, or they were grouped separately, or the definition of LTBI was stated as asymptomatic; "No" if it was unclear that active TB and people with TB symptom were excluded; and "Unclear" if only active TB or people with TB symptom were excluded or grouped. Test conduct bias Q4: Was the study conducted to compare QFT-PLUS with QFT-GIT, T.SPOT.TB and TST tests??
We scored "Yes" if the study was conducted to compare QFT-PLUS with QFT-GIT, T.SPOT.TB and TST tests?, "No" if the study was not conduced to compare QFT-PLUS with QFT-GIT, T.SPOT.TB and TST tests?; "Unclear" if this was not stated or stated inadequately. Q5: Was how the tests were conducted and interpreted adequately described?
We scored "Yes" if the tests were conducted and interpreted adequately described, such as the cut-off, time interval of the results were read, and manufacturer information, or "performed as the manufacturer's guidelines" was stated; and "No" if those information were not stated or stated inadequately. Q6: Was there an appropriate interval between QFT-PLUS with QFT-GIT, T.SPOT.TB and TST tests? We scored "Yes" if the two tests were paired or performed within 3 days, or "paired" comparison, "head-to-head" comparison was reported, and "No" if the interval was more than 3 days and less than 4 weeks; "Unclear" if this was not stated. Q7: If a threshold is used, was it confirmed beforehand? We scored "Yes" if the threshold values are used and predetermined, "No" if no prior determination; "Unclear" if there is no description. Flow and outcome Q8: Were the results of two tests interpreted without knowledge of each other? We scored "Yes" if the results of two tests were interpreted without knowledge of each other, or one test was interpreted blinded to another; "No" if blinding to test results were not done; and "Unclear" if this was not stated. Q9: Were all patients included in the analysis? We answered this question by comparing the number of participants included in the study and the number of individuals included in the 2x2 tables, test agreement data, or flow diagram. We scored 'Yes' if the number of participants enrolled was stated and corresponded to the number included in the analysis or if exclusions were adequately described. We scored "No" if there were participants missing or excluded from the analysis and there was no explanation given. We scored "Unclear" if we could not tell, e.g. because the number of participants enrolled and/or number of participants included in the analysis was not clearly stated.